The invention relates to the use of 9-deoxy-2′,9-α-methano-3-oxa-4,5,6-trinor-3,7-(1′,3′-interphenylene)-13,14-dihydro-prostaglandin F1 (hereafter “Treprostinil”) or its derivative, or a pharmaceutically acceptable salt thereof, to treat foot ulcers, for example, in patients with diabetic neuropathy. This invention also relates to kits to be used for this purpose.
Treprostinil, also known as UT-15, is a known compound disclosed in U.S. Pat. No. 4,306,075 in example 33. Treprostinil is a synthetic analog of epoprostenol, a prostaglandin F1. The activities ascribed to the various compounds of this patent include inhibition of smooth muscle cell proliferation, inhibition of platelet aggregation, inhibition of cytokine secretion, reduction of gastric secretion, vasodialation and bronchodilation.
U.S. Pat. No. 5,153,222 discloses the use of Treprostinil and related compounds to treat pulmonary hypertension. U.S. Pat. No. 6,054,486 discloses the use of Treprostinil and related compounds to treat peripheral vascular disease, such as peripheral arterial occlusive disease and intermittent claudication. Patterson et al., Amer. J. of Cardiology, 75: 26A-33A (1995), have shown vasodilator effects of Treprostinil in patients with class III or class IV heart failure.
Clapp et al., Am. J. Respir. Cell. Mol. Biol., 26 (2): 194-201 (2002), have shown that Treprostinil inhibits proliferation of human pulmonary arterial smooth muscle cells. Raychaudhuri et al., J. Biol. Chem., 277 (36): 33344-8 (2002), have disclosed that Treprostinil inhibits inflammatory cytokine (tumor necrosis factor-α, interleukin-1β, interleukin-6, and granulocyte macrophage colony-stimulating factor) secretion and gene expression by human alveolar macrophages.
Approximately 15% of all diabetes patients will develop a foot ulcer at some point in their lives, see, e.g., Jeffccoate, W & Harding, K., 2003. Diabetic Foot Ulcers. The Lancet, 362; 154-51, incorporated hereby by reference in its entirety. There are many pathways for a diabetic foot ulcer to develop. In general, approximately 20% of patients with diabetes will develop a foot ulcer primarily as a result of inadequate arterial blood flow (peripheral arterial disease), 50% from diabetic neuropathy, and 30% from a combination of lower limb ischemia and diabetic neuropathy. Since not all methods suitable for treating ischemic lesions can necessarily be used to treat ulcers caused by diabetic neuropathy, the need exits to identify viable methods, as well as kits, that can be used to prevent and treat such ulcers. See, e.g., Margolis, D. Hoffstad, O, Allen-Taylor, L., and Berlin, J., 2002. Diabetic Neuropathic Foot Ulcers: The association of the wound size, wound duration and wound healing. Diabetes Care 25:1835-39, incorporated hereby by reference in its entirety.
In addition, the differences in healing between a vascular leg ulcer (including the foot) and a diabetic foot ulcer can be found in Kantor J, Margolis D. Expected Healing Rates for Chronic Wounds. Wounds 12 (6):155-158, 2000. For example, in a study with 260 patients with vascular leg ulcers (VLU) and 586 patients with diabetic foot ulcers (DFU), 32% VLU failed to heal after 24 weeks of good ulcer care, while 67% DFU failed to heal after 20 weeks of good ulcer care. Other references distinguishing these different ulcers can be found in Watkins, P., Brit. Med. J., 326:977-979 (2003), TransAtlantic Intersociety Consensus (TASC), J. Vasc. Surgery, v. 31, NI part 2, page S199 (2000), and Greenhalgh D G, Clin. Plast. Surg., 30:37-45 (2003), which are incorporated herein by reference in their entirety.
Diabetic neuropathy is a condition in which nerve damage from diabetes caused decreased sensation in the legs and feet. If a patient develops an open area from pressure or from a cut, the patient may not even feel the sore. Left untreated, the damaged area can develop a diabetic foot ulcer that is susceptible to polymicrobial infection that spreads rapidly and causes overwhelming tissue destruction. This infection process is the main reason for major amputation following ulceration in patients with predominantly neuropathic ulceration. Traditional treatment approaches to foot ulcers include desloughing and debridement, pressure relief (e.g., rest, special footwear and shoe inserts and casting), antibiotic treatment for infection and wound dressing. Although certain types of dressings sometimes can help to aid healing of the lesions, these treatments are often unsuccessful.
Neuropathic diabetic foot ulcers can be extremely painful, debilitating, and heal slowly. Thus, the need exists to identify viable methods, as well as kits, that can be used to prevent and treat such ulcers. The present invention satisfies this need and provides related advantages as well.